HHS SBIR RFA-HD-15-012

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HHS SBIR RFA-HD-15-012

The purpose of this FOA is to support projects that demonstrate the presence of protein biomarkers that are related to brain structure or neurological function in patients in the chronic stages of traumatic brain injury (CBI). The research will provide anatomical evidence for changes in neurological, cognitive or emotional status seen in the years that follow brain trauma, and may serve as surrogate markers for recovery or decline.

Background

The Centers for Disease Control and Prevention estimates that between 1.7 and 2.5 million traumatic brain injuries (TBI) occur in the United States each year. Estimates of the prevalence of disability from TBI varies, but is believed to be perhaps 3% of the population in the U.S. A single moderate or severe injury to the brain has long-term consequences. About 70% of mild TBIs are believed to have temporary or limited sequelae; however, both clinical and basic science evidence suggest that repeated mild TBIs occurring over an extended period of time (i.e. months or years) result in cumulative neurological and cognitive deficits. Repeated mild TBIs occurring within a short period of time (i.e., hours, days, weeks) can be catastrophic or even fatal.

The consequences of TBI include a wide range of functional changes that affect thinking, sensation, motor skills, language, and emotion. TBI is a leading cause of epilepsy, and increases the risk for neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, ALS and other brain disorders that become more prevalent with age. Data from the TBI Model Systems National Database, supported by the National Institute of Disability and Rehabilitation Research, suggest that functional deterioration is common for long-term global outcomes after TBI. Injury to the brain can evolve into a lifelong health condition, which can be termed chronic brain injury (CBI).

To improve function and maintain participation in society, CBI must be identified as early as possible in its course, and more actively managed clinically. Investigators in rehabilitation science and clinical practice acknowledge that brain trauma often leads to permanent impairments; however, research and intervention paradigms are often aimed at early post-injury periods. How can the long-term course be studied and modified? Unfortunately, it is not currently possible to predict the time course for functional change, or the deficits that may newly emerge or grow more serious. Use of blood-based biomarkers to assess deterioration, stability or improvement would assist in both researching and treating CBI. Design of pharmaceutical or psychosocial interventions for CBI is possible; however, end points for brain injury trials are often based on lengthy neuropsychological testing or subjective outcome scales. Development of biological markers using an easily obtained blood-based sample would greatly facilitate clinical trials of interventions for CBI, and speed up progress toward treatment.

Reports have been published of several blood-based biomarkers associated with acute stages of TBI. Protein markers that have been linked to TBI include tau, amyloids, myelin basic protein, neurofilament light and heavy polypeptides, spectrin breakdown products, ubiquitin c-terminal hydrolase isoenzyme L1, GFAP breakdown products, interleukins, neuron-specific enolase and S100beta. Also, there is wide interest in peripheral blood mononuclear small noncoding RNA molecules (microRNA), inflammatory response molecules, as well as the use of gene arrays for clues to other targets. To date, most of this exploration is aimed at stages of injury up to hours, days or perhaps even a few weeks after TBI. The clinical rationale for discovery of the acute biomarkers includes decision-making about return to play in sports, fitness for combat duty, or identification of patients for inclusion in clinical trials of neuroprotective agents. The same attention is required for CBI.

These acute stage studies could certainly inform the search for blood-based biomarkers of CBI, where a second wave of injury (i.e. apoptosis, necrosis, loss of white matter, glial scarring, inflammation) could well take place. The chronic stages of injury must be examined so that interventions can be instituted as soon as possible for patients who might be at risk for mental or physical deterioration. In addition, as with acute markers, biomarkers for changes in the longer term stages of injury may be used as secondary or surrogate outcomes in clinical trials of new pharmaceutical, device or rehabilitation therapies for CBI.

Areas of interest include but are not limited to:

Discover and demonstrate the pattern of brain-specific proteins levels in peripheral blood in patients with CBI

Confirm utility or specificity of blood-based markers through comparison of results for blood-based protein markers to imaging profiles and/or neuropsychological test in patients with CBI

Explore and validate new technologies such as gene arrays or other expression-based platforms to discover new blood-based biomarkers of CBI.

Develop new approaches to discover and validate non-protein biomarkers for CBI in peripheral blood including but not limited to lipid profiles, micro-RNAs, or GWAS study

Demonstrate effective assessment of protein or biological products characteristics of other body systems that may have diagnostic patterns of severity of CBI, such as adhesion molecules, growth factors, endocrine components, signaling pathways, or components of the immune system

Both adults and children (aged 21 years or less) may be included as subjects; however, blood-based biomarkers may be different for age groups and developmental stages throughout the lifespan. Applicants must provide clear justification for selection of biomarkers for particular patient populations, with age-appropriate controls.

The primary focus of the studies submitted in response to this FOA must concentrate beyond initial brain pathophysiology. The focus should not be on primary neurodegenerative or neurodevelopmental disorders per se. This FOA seeks only clinical research in living human subjects; studies in animal models or post-mortem specimens are not responsive to the FOA.